Imidazole derivatives for treating pain,inflammation and fever

ABSTRACT

COMPOUNDS OF THE CLASS OF 2-ALKYL-AND 2-CYCLOALKYL-4,5BIS-PHENYL-IMIDAZOLES, THE PHENYL GROUPS OF WHICH BEING SUBSTITUTED BY METHOXY, METHYL, HYDROXY, METHYLSULFONYL AND/OR CHLORO, AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF HAVE ANALGESIC, ANTIPHLOGISTIC AND ANTIPYRETIC ACTIVITY, THEY ARE ACTIVE INGREDIENTS OF PHARMACEUTICAL COMPOSITIONS AND CAN BE USED FOR THE RELIEF AND REMOVAL OF PAIN AS WELL AS FOR THE TREATMENT OF RHEUMATIC, ARTHRITIC AND OTHER INFLAMMATORY DISEASES.

United States Patent Oflice 3,784,691 Patented Jan. 8, 1974 US. Cl.424-273 9 Claims ABSTRACT OF THE DISCLOSURE Compounds of the class of2-alkyland 2-cycloalkyl-4,5- bisphenyl-imidazoles, the phenyl groups ofwhich being substituted by methoxy, methyl, hydroxy, methylsulfonyl and/or chloro, and pharmaceutically acceptable acid addition salts thereofhave analgesic, antiphlogistic and antipyretic activity; they are activeingredients of pharmaceutical compositions and can be used for therelief and re moval of pain as well as for the treatment of rheumatic,arthritic and other inflammatory diseases.

This is a division of application Ser. No. 102,131, filed Dec. 28, 1970.

DETAILED DESCRIPTION The present invention relates to imidazolederivatives having valuable pharmacological properties, to processes fortheir production, to pharmaceutical compositions containing thesecompounds and to their use.

More particular, the present invention relates to compounds of theformula wherein R, is alkyl having 2 to 6 carbon atoms or cycloalkylhaving 3 to 6 carbon atoms,

R is met-hoxy, methyl or methylsulfonyl, and

R is methoxy, methyl, hydrogen or chloro,

and the pharmaceutically acceptable acid addition salts thereof.

It has now been found that these new substances possess valuablepharmacological properties, especially analgesic, antiphlogistic, andantipyretic activity, combined with a favorable therapeutic index, andnegligible gastrointestinal side effects. The following are mentioned asexamples of such pharmacologically valuable compounds of Formula I:

2-isopropyl-4,5-bis- (p-met-hoxyphenyl -imidazole,

2-ethyl-4,5-bis- (p-methoxyphenyl -imidazole,

2-cyclopropyl4,5-bis- (p-methoxyphenyl -imidazole,

2-tert.butyl-4 [p- (methylsulphonyl -phenyl] -5 (4) phenyl-imidazole,and

2-tert.butyl-4 5 p-hydroxyphenyl) 5 (4 -phenyl-imidazole.

The analgesic activity of the new imidazole derivatives of the GeneralFormula I is demonstrated, for example, on the mouse by the methoddescribed by E. Siegmund, R. Cadmus and G. Lu, Proc. Soc. Exp. Biol.Med. 95, 729 (1957), whereby the amount of substance is determined whichis required to prevent the syndrome produced by intraperitonealinjection of 2-phenyl-1,4-benzoquinone. The antiphlogistic activity ofthe new imidazole derivatives of the General Formula I when administeredorally is shown, for example, on rats in the bolus alba oedema testaccording to G. Wilhelmi, Jap. J. PharmacoL, 15, 187 (1965).

The antipyretic activity is determined by the compounds of the GeneralFormula I being administered orally, in suitable dosages, to groups ofrats which had received, 16-18 hours previously, an intramuscularinjection of a suspension of 15% of bakers yeast with 1% of tragacanthand 1% of sodium chloride in distilled water, the amount being 1 ml. perg. of body weight. The fever temperatures produced by the yeast weremeasured rectally one hour and also half an hour before administrationof the test substances, and then half-hourly from half an hour to 5hours after administration of the test substances; and the maximumtemperature fall as well as the arithmetical mean temperature fallduring the 5 hours after administration of the test substances wasdetermined as a basis of comparison in relation to the average of thetwo measurements taken before administration.

In the above described tests the compounds of the invention aredemonstrated to be active in dosages of between about 2 and about 200mg./ kg. The toxicity of the compounds of the invention is of favorablelow order.

The new imidazole derivatives of the General Formula I and theirpharmaceutically acceptable addition salts with inorganic and organicacids are suitable as active substances for medicaments which can beadministered orally, rectally or parenterally for the relief and removalof pains of varying origin, as well as for the treatment of rheumatic,arthritic and other inflammatory diseases.

In the imidazole derivatives of the General Formula I and in thecorresponding starting materials given below, R is, eg the ethyl,propyl, isopropyl, butyl, sec.butyl, tert.butyl, pentyl, isopentyl,tert.pentyl, neopentyl, l-methylbutyl, l-ethylpropyl, hexyl, isohexyl,l-methylpentyl, 1- ethylbutyl or 1,1-dimethylbutyl group, thecyclopropyl, cycolbutyl, cyclopentyl, or cyclohexyl group.

The new imidazole derivatives of the General Formula I and their acidaddition salts are produced by condensing a substituted benzil of theGeneral Formula II:

a (11) wherein R and R have the meanings given under Formula I with the,at least, double molar amount of ammonia, and/or a greater excess offormamide, and an aldehyde of the General Formula III:

(III) wherein R, has the meaning given under Formula I; and, optionallyconverting the obtained imidazole derivative into an addition salt withan inorganic or organic acid. For example, condensation is performedwith ammonia in a lower alkanoic acid, especially acetic acid or formicacid, or in a carboxylic acid R -COOH, at the boiling temperature of thereaction mixture, and the ammonia is used in a large excess in the formof the corresponding alkanoic acid salt. The aldehyde can be used in anamount which is substantially equimolar with respect to the substitutedbenzil of the General Formula II, or it can also be used in excess, inorder to obtain the most favorable result in a particular case, takinginto account the accessibility of the starting materials and case ofpurification of the final material. The reaction time is generallybetween one and 24 hours. Purification of the free imidazole derivativesobtained by the aforementioned process or by further processes, isperformed, e.g. by recrystallization from benzene, toluene, or a loweralkanol. If necessary, the imidazole derivatives melting mostly above100 C. are subsequently dried, for the removal of crystal-solvent, inhigh vacuum at 100 C. and higher. A further possibility of obtainingpure imidazole derivatives is the conversion (dealt with in more detailbelow) of a crude product into an acid addition salt, optionallyrecrystallization of the latter and, finally, again liberation of theimidazole derivative of the General Formula I.

According to a modification of the aforementioned process, a substitutedbenzil of the General Formula II is heated with a larger excess offormamide and with an aldehyde of the General Formula III to 180 to 200C.; and, optionally, the obtained imidazole derivative is converted intoan addition salt with an inorganic or organic acid. In the case of thisprocess modification, a part of the formamide decomposes to ammonia, andhence renders possible the formation of the imidazole derivatives of theGeneral Formula I, analogously to the first mentioned embodiment. Thereaction is carried out, e.g. by refluxing for 2-6 hours a substitutedbenzil of the General Formula II with the equimolar amount, or with anexcess, of aldehyde of the General Formula HI in formarnide, the amountof formamide being approximately to 25 times that of the two otherreactants; or with a mixture of formamide and dimethylformamide.

According to a second process, the imidazole derivatives of the GeneralFormula I and their acid addition salts are produced by condensing asubstituted benzoin of the General Formula IV:

Q Ra h (IV) wherein R and R have the meanings given under Formula I, inthe presence of an oxidizing agent usual for conversion of thesubstituted benzoin into the correspondingly substituted benzil, withthe, at least, double molar amount of ammonia, and with an aldehyde ofthe above given General Formula III in which R has the meaning givenunder Formula I; and, optionally, converting the obtained imidazolederivative into an addition salt with an inorganic or organic acid.Preferably used as oxidizing agent is an organic copper(II)-salt such ascopper(II)- acetate or -citrate, whereby the formed imidazole derivativeof the General Formula I precipitates as copper salt, and can befiltered off. The ammonia is preferably used in a large excess, andoxidation and simultaneous condensation are preferably performed, e.g.in a lower alkanol, such as methanol or ethanol, at 30 to 100 C. or atthe boiling temperature of the alkanol. The reaction duration ispreferably between half an hour and hours; for example, the reactioncomponents are boiled for ca. 4 hours in methanol. The desired imidazolederivative is liberated, from the directly obtained copper salt, in theusual manner, e.g. by reaction with hydrogen sulphide in a lower alkanolin the heat.

According to a third process, the imidazole derivatives of the GeneralFormula I and their acid addition salts are obtained by reacting in theheat an amide of the General Formula V:

wherein R R and R have the meaning under Formula I with an ammonium saltof a lower alkanoic acid or with formamide; and, optionally, convertingthe obtained imidazole derivative into an addition salt with aninorganic or organic acid. For example, an amide of the General FormulaV is refluxed with excess ammonium acetate in glacial acetic acid, orwith excess ammonium formiate in formic acid, for one to ca. 24 hours;or it is heated with excess formamide for ca. 26 hours to to 200 C.,whereby the desired ring closure is elfected by partial decomposition ofthe formamide with liberation of ammonia. In certain cases, betteryields are obtained by performing condensation, instead of with ammoniumacetate in glacial acetic acid, with the ammonium salt of alkanoic acidR COOH in this acid as the reaction medium.

The starting materials of the General Formula V are produced, e.g. byacylation of 2-amino-2-phenylacetophenones containing in one phenylgroup in p-position the methoxy or methyl group, and in the other phenylgroup either no substituents or, in any position, the methoxy or methylgroup, e.g. 2-amino-4-methoxy-2- phenylacetophenone or 2 amino 4'methoxy-Z-(p-methoxyphenyl)-acetophenone, with alkanolic acid chlorideshaving 37 carbon atoms, or with cycloalkanecarbonyl chlorides having 4-7carbon atoms, or with the corresponding acyl bromides or anhydrides.

A fourth process for the production of the imidazole derivatives of theGeneral Formula I and their acid addition salts consists in condensing areactive ester of a substituted benzoin of the above given GeneralFormula IV wherein R and R have the meanings given under Formula I withan amidine of the General Formula VI:

HN (VI) wherein R has the meaning given under Formula I; and,optionally, converting the obtained imidazole derivative into anaddition salt with an inorganic or organic acid. Condensation can beefiected by the reactants being merely heated in an inert solvent atmoderately elevated temperatures, e.g. by boiling in chloroform.

In order to avoid liberation of the amidines from their more stablehydrochlorides before the reaction, the reaction is advantageouslyperformed in a two-phase system consisting of a solution of a reactiveester of the substituted benzoin, e.g. bromide, in an inert organicsolvent such as, e.g. chloroform, and an aqueous solution of thehydrochloride of an amidine of the General Formula VI. With heating andvigorous stirring, diluted aqueous potassium or sodium hydroxidesolution, in overall the double-molar amount, is added dropwise inorder, on the one hand, to liberate the amidine and, on the other hand,to bind the acid being liberated on ring closure. Suitable reactiveesters of the substituted benzoins of the General Formula IV are, inparticular, the bromides and chlorides, and also esters of loweralkanesulphonic acids and arenesulphonic acids, such as methanesulphonicacid esters and p-toluenesulphonic acid esters. Mentioned as examples ofsuch starting materials are 2-halogen-2-phenylacetophenones substitutedin p-position of the one phenyl group and, optionally, also in anydesired position of the other phenyl group by a methoxy or methyl group,such as 2-bromoand 2-chloro-4'-methoxy-2-(p-methoxyphenyl)-acetophenone, 2-bromoand 2-chloro-4'-methoxy-2-phenylacetophenone,2-bromoand 2-chloro-2-(p-methoxyphenyl)-acetophenone, 2-bromoand2-chloro-4'-methyl- 2 (p tolyl) acetophenone, 2 -bromoand 2-chloro-4-methyl-2-phenylacetophenone, as well as 2-b1'omoand2-chloro-2-(p-tolyl)-acetophenone.

According to a fifth process, the compounds of the General Formula I areobtained by heating an oxazole of the General Formula VII:

wherein R R and R have the meanings given under Formula I with ammoniaand/or formamide. For example, an oxazole of the General Formula VII isheated with a mixture of liquid ammonia and formamide in an autoclave totemperatures of ca. 180 C. to 220 C., or a mixture of the stated oxazolewith formamide is heated, for some time, e.g. one to hours, to theboiling or decomposition temperature of the formamide.

The oxazoles of the General Formula VII serving as starting materialsare, for their part, new compounds. They are produced, e.g. by firstlyreacting benzoins of the above given General Formula IV substitutedcorresponding to the definition for R and R with halides of alkanoicacids having 3-7 carbon atoms, or cycloalkanecarboxylic acids having 47carbon atoms, to give the corresponding esters. These are allowed toreact with an ammonium salt of a lower alkanoic acid in the heat; forexample, they are refluxed with excess ammonium acetate in glacialacetic acid for ca. 2-10 hours, whereby the desired oxazole is formed.

According to a further process, the oxazoles of the General Formula VIIare obtained by allowing an amide of the above given General Formula Vwherein R R and R have the meanings given under Formula 1 to react witha dehydrating agent. For example, the stated amides are refluxed withthionyl chloride in the presence or absence of an inert solvent such as,e.g. benzene, until the evolution of hydrogen chloride has ceased; orconcentrated sulphuric acid is allowed to act for a short time attemperatures of 0 C. to room temperature.

A third access to the oxazoles of the General Formula VII consists inreacting an alkanoic acid nitrile having 3-7 carbon atoms, or acycloalkanecarbonitrile having 47 carbon atoms, with a substitutedbenzoin of the above given General Formula IV wherein R and R have themeanings given under Formula I, in the presence of a mineral acid. Forexample, concentrated sulphuric acid is allowed to act on an equimolarmixture of the stated starting materials for a short time attemperatures between 0 and 30 C., or polyphosphoric acid for ca. 30minutes to several hours at ca. 80 to 120 C.

Further processes for the production of oxazoles of the General FormulaVII are the condensation of reactive esters, especially hydrohalic acidesters, of benzoins of the General Formula IV with alkanoic acid amideshaving 3-7, or cycloalkanecarboxamides having 47 carbon atoms, byheating to temperatures between ca. 130 and 170 C.; and also thereaction of the stated reactive esters of benzoins of the GeneralFormula IV with tin- (IV)-chloride complexes of the already mentionedalkanoic acid nitriles having 3-7 carbon atoms, or cycloalkanecarbonitriles having 47 carbon atoms, at room temperature to ca.100 C.

The imidazole derivatives of the General Formula I obtained by theprocess according to the invention are subsequently optionallyconverted, in the usual manner, into their addition salts with inorganicand organic acids. For example, to a solution of an imidazole derivativeof the General Formula I in an organic solvent is added the acid desiredas salt component, or a solution of the acid. Preferably chosen for thereaction are organic solvents in which the formed salt does not readilydissolve, so that it can be separated by filtration; or to a solventhaving a good dissolving power is added one having appreciably lowerdissolving power. Suitable sol vents or solvent combinations are, e.g.methanol, acetone methyl ethyl ketone, ethyl acetate, oracetone/ethanol, methanol/ether, ethanol/ether, or ethyl acetate/ether.Furthermore, it is also possible to dissolve equimolar or equivalentamounts of an imidazole of the General Formula I and of the acid desiredas salt component in one of the aforementioned solvents, and toconcentrate the solution in vacuo.

Moreover, it is possible to produce hydrochlorides, e.g. by intensiveshaking or stirring of an organic solution of an imidazole derivative ofthe General Formula I, e.g. and ethyl acetate solution, with moderatelyconcentrated aqueous hydrochloric acid, and recrystallization of theprecipitated crude hydrochlorides, e.g. from ethanol.

For use as medicaments it is possible to use, instead of the freeimidazole derivatives, pharmaceutically acceptable acid addition salts,i.e. salts with such acids of which the anions are not toxic in thedosage amounts concerned. Furthermore, it is of advantage if the saltsto be used as medicaments crystallize well and not, or only slightly,hygroscopic. For salt formation with imidazole derivatives of theGeneral Formula I it is possible to use, e.g. hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonicacid, ethanesulphonic acid, ,B-hydroxyethanesulphonic acid, acetic acid,malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, benzoic acid, salicyclic acid,phenylacetic acid, madelic acid and embonic acid.

The new imidazole derivatives of the General Formula I and theirpharmacologieally acceptable acid addition salts are preferablyadministered orally or rectally. The dosage depends on the mode ofadministration, on the species and age, and on the individual condition.The daily dosages of the free imidazole derivatives, or ofpharmaceutically acceptable salts thereof, vary between 0.5 mg./kg. and50 mg./ kg. for mammals. Suitable dosage units such as drag-es, tablets,suppositories or ampoules, preferably contain an imidazole derivative ofthe General Formula I, or a pharmaceutically acceptable acid additionsalt thereof, in an amount of 025-5 mg./kg. of body weight of thespecies to be treated.

Dosage units for oral administration preferably contain an activesubstance between 10 and of a compound of the General Formula I, or of apharmaceutically acceptable salt of such a compound. They are producedby combining the active substance, e.g. with solid pulverluent carrierssuch as, lactose, saccharose, sorbitol, mannitol; starches such aspotato starch, maize starch or amylopectin, also laminaria powder orcitrus pulp powder; cellulose derivatives or gelatine, optionally withthe addition of lubricants such as magnesium or calcium stearate, orpolyethylene glycols, to form tablets or drage cores. The drage coresare coated, e.g. with concentrated sugar solutions which may alsocontain, e.g. gum arabic, talcum and/or titanium dioxide; or they arecoated with a lacquer dissolved in readily volatile organic solvents ormixtures of solvents. Dyestuffs can be added to these coatings, e.g. foridentification of the various dosages of active substance. Furthersuitable oral dosage units are hard gelatine capsules as well as softclosed capsules made from gelatine and a softener, such as glycerol. Thehard gelatine capsules, preferably contain the active substance as agranulate in admixture with lubricants such as talcum or magnesiumstearate, and, optionally stabilizers such as sodium metabisulphite (NaS O or ascorbic acid. In soft capsules, the active substance ispreferably dissolved or suspended in suitable liquids such as liquidpolyethylene glycols, whereby likewise stabilizers may be added.

Suitable dosage units for rectal administration are, e.g. suppositoriesconsisting of a combination of an active substance with a suppositoryfoundation substance based on natural or synthetic triglycerides (e.g.cocoa butter),

polyethylene glycols or suitable higher fatty alcohols; and gelatinerectal capsules containing a combination of the active substance withpolyethylene glycols.

Further suitable means of administration are, e.g. lotions, tincturesand ointments, prepared with the usual auxiliaries, for percutaneousadministration.

The following prescriptions further illustrate the production of anumber of typical preparations:

(a) An amount of 1000 g. of 2-ethyl-4,5-bis-(p-methoxyphenyl)-imidazoleis mixed with 550 g. of lactose and 292 g. of potato starch; the mixtureis then moistened with an alcoholic solution of 8 g. of gelatine, andgranulated through a sieve. After drying of the granulate, 60 g. ofpotato starch, 60 g. of talcum and 10 g. of magnesium stearate and 20 g.of highly dispersed silicon dioxide are mixed in, and the mixture ispressed to form 10,000 tablets each weighing 200 mg. and each containing100 mg. of active substance. If required, the tablets may be providedwith grooves for a more precise adjustment of the dosage amount. Asactive substances, it is also possible to use, e.g. 500 g. of2-tert.butyl-4(5)-(p-methoxyphenyl) 5 (4) -phenyl-imidazole, or 500 g.of 2-cyclopropyl-4,5-bis-(p methoxyphenyl) imidazole, whereby 10,000tablets each weighing 150 mg. and each containing 50 mg. of activesubstance are obtained.

(b) An amount of 100 g. of2-isopropyl-4,5-bis-(p-methxyphenyl)-imidazole is well mixed with 16 g.of maize starch and 6 g. of highly dispersed silicon dioxide. Themixture is moistened with a solution of 2 g. of stearic acid, 6 g. ofethyl cellulose and 6 g. of stearin in ca. 70 ml. of isopropyl alcohol;and then granulated through a sieve III (Ph. Helv. V). The granulate isdried for ca. 14 hours, and then put through sieve III-IIIa. It isafterwards mixed with 16 g. of maize starch, 16 g. of talcum and 2 g. ofmagnesium stearate, and the mixture pressed to form 1000 drage cores.These are coated with a concentrated syrup of 2 g. of lacca, 7.5 g. ofgum arabic, 0.15 g. of dyestutf, 2 g. of highly dispersed silicondioxide, 25 g. of talcum and 53.35 g. of sugar, and then dried. Theobtained drage each weight 260 mg. and each contain 100 mg. of activesubstance. It is also possible to use as active substance, e.g. the sameamount of 2-ethyl-4,5-bis- (p-methoxyphenyl)-imidazole.

(0) An amount of 50 g. of2-cyclopropy-4,5-bis-(pmethoxyphenyl)-imidazole and 1950 g. of finelyground suppository foundation substance (e.g. cocoa butter) isthoroughly mixed and then melted. From the melt, maintained homogeneousby stirring, are poured 1000 suppositories each weighing 2 g. Eachsuppository contains 50 mg. of active substance.

(d) 60 g. of polyoxyethylene anhydrosorbit-monostearate, 30 g. ofanhydrosorbit-monostearate, 150 g. of parafiin oil and 120 g. of stearylalcohol are melted together; to the melt are added 50 g. of2-tert.butyl-4(5)- (p hydroxyphenyl) (4) phenylimidazole (finelyground), and 590 ml. of preheated water at 40 are then added to form anemulsion. The emulsion is stirred until it has cooled to roomtemperature, and then filled into tubes.

The following examples further illustrate the production of the newimidazole derivatives of the General Formula I, but the examples in noway limit the scope of the invention. The temperatures are given indegrees centigrade.

EXAMPLE 1 (a) The mixture of 13.5 g. (0.050 mole) of p-anisil, 3.96 g.(0.055 mole) of isobutyraldehyde, 27.0 g. (0.35 mole) of ammoniumacetate and 130 ml. of glacial acetic acid is refluxed for 15 hours, andsubsequently poured, with vigorous stirring, into a mixture of 350 g. ofice and 270 ml. of concentrated aqueous ammonia solution. The crystalmass is extracted with ethyl acetate, and the organic phase washedneutral with saturated sodium chloride solution, dried with sodiumsulphate, and concentrated by evaporation. The residue is recrystallizedfrom ethyl acetate, and dried in high vacuum at Thus obtained is2-isopropyl 4,5 bis (p methoxyphenyl)- imidazole as White crystals, M.P.195-196". Yield 8.8 g., 55% of the theoretical value.

The following imidazole derivatives are obtained analogously by using,instead of the isobutyraldehyde, 0.055 mole of the correspondingaldehydes:

2-ethyl-4,5-bis(p-methoxyphenyl) imidazole, M.P. 172 (from toluene) with3.19 g. of propionaldehyde;

2-propyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P.

182 (from ethyl acetate), with 3.96 g. of butyraldehyde;

2-butyl-4,5-bis-(p-methoxyphenyl) imidazole, M.P. 175- 176 (from ethylacetate), with 4.73 g. of valeraldehyde;

2-isobutyl-4,5-bis-(p methoxyphenyl) imidazole, M.P.

166-1 68" (from benzene), with 4.73 g. of isovaleraldehyde;

2-tert.butyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P.

167168 (from benzene), with 4.73 g. of pivalaldehyde;

2-pentyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P.

137-138" (from ethyl acetate), with 5.50 g. of hexanal;

2-hexyl-4,5-bis- (p-methoxyphenyl)-imidazole, M.P.

145-147 (from toluene), with 6.27 g. of heptanal;

2-( 1,1-dimethylbutyl)-4,5-bis- (p-methoxyphenyl) imidazole, M.P.120-121 (from toluene/petroleum ether), with 6.27 g. of2,2-dimethylvaleraldehyde;

2-cyclopropyl-4, 5 -bis- (p-methoxyphenyl -imidazole,

M.P. 189--191 (from toluene), with 3.85 g. ofcyclopropanecarboxaldehyde;

2-cyclohexyl-4,5-bis- (p-methoxyphenyl -imidazole,

M.P. 194195 (from benzene), with 6.16 g. of cyclohexanecarboxaldehyde.

Likewise analogously obtained are the following imidazoles bycondensation of 0.050 mole of the stated substituted benzils with 0.055mole of the stated aldehydes:

2-ethyl-4 (5) (p-methoxyphenyl) -5 4) -phenyl-imidazole, M.P. 161163(from toluene), from 12.0 g. of 4-methoxybenzil and 3.19 g. ofpropionaldehyde;

2-isopropyl-4 (5 (p-methoxyphenyD-S (4) -phenyl-imidazole, M.P. 189-191(from toluene), from 12.0 g. of 4-methoxybenzil and 3.96 g. ofisobutyraldehyde;

2-butyl-4 (5 (p-methoxyphenyl)-5 4) -phenyl-imidazole, M.P. 162-163(from ethanol), with 12.0 g. of 4-methoxybenzil and 4.73 g. ofvaleraldehyde;

2-cyclopropyl-4 (5 (p-methoxyphenyl -5 (4 )-phenylimidazole, M.P. 162163(from toluene), from 12.0 g. of 4-methoxybenzil and 3.85 g. ofcyclopropanecarboxaldehyde;

2tert.butyl-4,5-bis(p-tolyl)imidazole, M.P. 204-206 (from toluene), from11.9 g. of p-tolyl and 4.73 g. of pivaldehyde;

2-isopropyl-4(5)-(p-tolyl)-5(4)-phenyl-imidazole, M.P.

209-210 (from toluene), from 11.2 g. of 4-methylbenzil and 3.96 g. ofisobutyraldehyde;

2-tert.butyl-4 (5 (p-tolyl) -5 4) -phenyl-imidazole, M.P.

154-156 (from toluene), from 11.2 g. of 4-methylbenzil and 4.73 g. ofpivalaldehyde;

2-tert.butyl-4 5 p-methoxyphenyl) -5 4) (p-tolyl) imidazole, M.P.171-173 (from toluene), from 12.7 g. of 4-methoxy- '-methylbenzil [see(b) below] and 4.73 g. of pivalaldehyde;

2-tert.butyl-4 (5) (p-methoxyphenyl) -5 (4 (m-tolyl)- imidazole, M.P.-187 (from toluene), from 12.7 g. of 4-methoxy-3-methylbenzil [see (a)above and (b) below] and 4.73 g. of pivalaldehyde;

2-tert.butyl-4 5 (p-methoxyphenyl)-5 4) (o-tolyl)- imidazole, M.P.156-158 (from toluene), from 12.7 g. of 4-methoxy-2'-methylbenzil [see(a) above and (b) below] and 4.73 g. of pivalaldehyde.

The substituted benzils required for the last three imidazoles areproduced as follows:

(b) An amount of 48 g. of powdered aluminium chloride is addedportionwise at 2 to 10, within 45 minutes, to the mixture of 50.0 g.(0.3 mole) of (m-tolyl)- acetyl chloride, 39.0 g. (0.36 mole) of anisoleand 195 ml. of carbon disulphide. The red mixture is stirred for 20minutes at to 10, and subsequently for 90 minutes at 20-25". It is thenrefluxed for 15 minutes, cooled and poured onto a mixture of 500 g. ofice and 100 ml. of N hydrochloric acid; it is then allowed to stand and,after 2 hours, extracted with benzene. The organic phase is washed with5 N hydrochloric acid and saturated sodium chloride solution, dried oversodium sulphate, and concentrated by evaporation. The obtained4'-methoxy- 2 (m-tolyl)-acetophenone melts, after recrystallization fromethanol, at 64-66".

4'-methoxy 2 (o-tolyD-acetophenone, M.P. 88-90 (from ethanol) isproduced analogously using 50.0 g. (0.3 mole) of (o-tolyl)-acetylchloride.

(0) The solution of 24.0 g. (0.10 mole) of 4'-methoxy- 2 (m-tolyl)acetophenone in 250 ml. of dimethylsulphoxide and 7.5 ml. ofconcentrated hydrogen bromide is stirred for hours at 70-80, andsubsequently poured into 3 litres of water. The yellow suspension isextracted with ethyl acetate; the organic phase is washed with saturatedsodium chloride solution, dried over sodium sulphate, and concentratedby evaporation. Thus obtained is i-methoxy-y-methylbenzil, M.P. 55-57(from ethano The following are produced analogously:

4-methoxy- -methylbenzil, M.P. 108-110 (from ethanol), starting with24.0 g. of 4'-methoxy-2- (p-tolyl)- acetophenone [M.P. 90-90.5 (fromethanol), cp. J. Amer. Chem. Soc., 76, 3721-3722 (1954)];4-methoxy-2-methylbenzil, M.P. Ill-113 (from ethanol, starting with 24.0g. of 4'-methoxy-2-(o-tolyl)- acetophenone.

EXAMPLE 2 The mixture of 11.5 g. (0.048 mole) of 4-methoxybenzil, 5.45g. (0.063 mole) of pivalaldehyde, 50.0 g. (0.65 mole) of ammoniumacetate and 100 ml. of glacial acetic acid is refluxed for hours, andsubsequently poured, with vigorous stirring, into a mixture of 300 g. ofice and 240 ml. of cone. aqueous ammonia solution.

I The crystal mass is extracted with ethyl acetate, the organic phasewashed with saturated sodium chloride solution until neutral, dried'with sodium sulphate, and concentrated by evaporation. The residue iscrystallized from toluene, and dried in high vacuum at 110, whereby 2-tert.-butyl-4(5)-(p-methoxyphenyl 5(4) phenyl-imidazole, M.P. 193-194,is obtained.

EXAMPLE 3 An amount of 50.0 g. (0.18 mole) of p-anisoin is dissolved,with heating, in 750 ml. of methanol. To the solution are added, at30-35", 36.6 g. (0.18 mole) of copper(II)-acetate-monohydrate, followedby 14.4 g. (0.20 mole) of isobutyraldehyde. Within 10 minutes are addeddropwise 375 ml. of concentrated aqueous ammonia solution; the solutionis then refluxed for 3 hours, and filtered hot. The copper salt of thedesired imidazole,

obtained as suction-filter residue, is washed twice with 50 ml. of hotmethanol each time, and afterwards suspending in 1000 ml. of ethanol.The ethanolic suspension is saturated at 80 with hydrogen sulphide; andafter 3 hours stirring at 80, the hot suspension is filtered ofi undersuction to remove the copper sulphide. The filtrate is concentrated byevaporation, the residue recrystallized from ethyl acetate, and dried inhigh vacuum at The obtained2-isopropyl-4,5-bis(p-methoxyphenyl)-imidazole melts at l95-196.

(a) The following are produced analogously from 0.18 mole of thecorrespondingly substituted benzoins and 0.20 mole of the correspondingaldehydes:

2-ethyl-4,5-bis-(pmethoxyphenyl)-imidazole, M.P.

172" (from toluene), starting with 50 g. of p-anisoin and 11.6 g. ofpropionaldehyde;

2-propyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P. 180- 182" (from ethylacetate), starting with 50 g. of panisoin and 14.4 g. of butyraldehyde;

2-butyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P. 176 (from ethylacetate), starting with 50 g. of panisoin and 17.2 g. of valeraldehyde;

2-isobutyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P.

166-168 (from benzene), starting with 50 g. of panisoin and 17.2 g. ofisovaleraldehyde;

2-pentyl-4,5-bis- (p-methoxyphenyl)-imidazole, M.P. 137- 138 (from ethylacetate), starting with 50 g. of panisoin and 20.0 g. of hexanol;

2-cyclopropyl-4,5-bis-(p-methoxyphenyl)-imidazo1e, M.P.

189-191 (from toluene), starting with 50 g. of panisoin and 14.0 g. ofcyclopropanecarboxaldehyde;

2-cyclohexyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P.

194-195" (from benzene), starting with 50 g. of panisoin and 22.4 g. ofcyclohexanecarboxaldehyde;

2-isopropyl-4(5 (p-methoxyphenyl) -5 (4) phenyl-imidazole, M.P. 189-191(from toluene), starting with 43.2 g. of 4-methoxybenzoin and 14.4 g. ofisobutyraldehyde;

2-butyl-4 (5 (p-methoxyqahenyl) -5 (4) -phenyl-imidazole, M.P. 162-163"(from ethanol), starting with 43.2 g. of 4-methoxybenzoin and 17.2 g. ofvaleraldehyde;

2-tert.butyl-4(5 (p-methoxyphenyl) -5 (4) -phenyl-imidazole, M.P.193-194 (from toluene), starting with 43.2 g. of 4-methoxybenzoin and17.2 g. of pivalaldehyde;

2-cyclopropyl-4 (5 )-(p-methoxypheny1)-5 (4) -phenylimidazole, M.P.192-193 (from toluene), starting with 43.2 g. of 4-methoxybenzoin and14.0 g. of cyclopropanecarboxaldehyde;

2-tert.butyl-4,5-bis-(p-tolyl)-imidazole, M.P. 204-206 (from toluene),starting with 42.8 g. of p-toluoin and 17.2 g. of pivalaldehyde.

(b) The following further compounds may also be prepared analogously:

2-tert.butyl-4 5 (p-hydroxyphenyl) -5 (4) -phenylimidazole, M.P.'190-192, starting with 41.0 g. of 4'- hydroxybenzoin and 17.2 g. ofpivalaldehyde; 2-tert.-butyl-4(5 (p-methoxyphenyl-5 (4)-(p-chlorophenyl)-imidazole, M.P. 148-150", starting 'with 49.8

g. of 4-methoxy-4'-chlorobenzoin and 17.2 g. of pivalaldehyde;2-tert.butyl-4( 5 (p-methylsulphonylphenyl) -5 (4) phenylimidazole, M.P.215-217", starting with 52.2 g.

of 4-methylsulphonylbenzoin and 17.2 g. of pivalaldehyde.

The last-mentioned starting material: 4-methyl-sulphonylbenzoin, isproduced as follows: An amount of 80 g. (0.227 mole) of2-bromo-4-methyl-sulphonyl-2- phenylacetophenone is refluxed togetherwith 80 g. of sodium acetate and 900 ml. of glacial acetic acid for 5hours. The reaction mixture is concentrated in a rotary evaporator,taken up in ether, and washed with water.

The organic phase is briefly shaken with 2 N sodium hydroxide solution;it is subsequently washed with ice-cold dilute hydrochloric acidsolution, dried over sodium sulphate, and concentrated by evaporation.The residue is recrystallized from ethylacetate/ether/petroleum ether,M.P. 116119.

EXAMPLE An amount of 7.10 g. (0.020 mole) ofN-[4-methoxya-(p-methoxyphenyl) phenacyl] valeramide [cf. (a) above] isrefluxed with 13.1 g. (0.17 mole) of ammonium acetate in 60 ml. ofglacial acetic acid for 14 hours. The brown solution is then poured onto 120 ml. of concentrated ammonia and 120 g. of ice, and extracted withethyl acetate. The organic phase is separated, washed with saturatedsodium chloride solution until neutral, dried over sodium sulphate, andconcentrated by evaporation. The residue is crystallized from ethylacetate, whereby 5.31 g. (79% of the theoretical value) of 2-butyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P. 175-176, are obtained.

The following imidazoles are obtained analogously, using 0.020 mole ofthe corresponding amides:

2-ethyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P. 170- 172 (fromtoluene), from 6.54 g. of N-[4-methoxy-a-(p-methoxyphenyl)-phenacyl]-propionamide;

2-isopropyl-4,5-bis-(p-methoxyphenyl) imidazole, M.P.

195-196 (from ethyl acetate), from 6.82 g. of N-[4- methoxy-a(pmethoxyphenyl) phenacyl] isobutyramide;

2-isobutyl-4,5-bis-(p methoxyphenyl) imidazole, M.P.

166168 (from benzene), from 7.10 g. of N-[4-methoxy-a- (p-methoxyphenyl-phenacyl] -isovaleramide;

2-hexyl-4,S-bis (p methoxyphenyl) imidazole, M.P.

145147 (from toluene), from 7.66 g. ofN-[4-methoxy-a-(p-methoxyphenyl)-phenacyl]-heptanamide;

2-(1,1-dimethylbutyl) 4,5 bis (p-methoxyphenyl-imidazole, M.P. 120-121(from toluene/petroleum ether), from 7.66 g. of N[4-methoxy-a-(p-methoxyphenyl)- phenacyl]-2,Z-dimethyl-valeramide;

2-cyclopropyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P.

189-19l (from toluene), from 6.78 g. of N-[4-methoxy-a-(p methoxyphenyl)phenacyl] cyclopropanecarboxamide;

2-ethyl-4 (5 (p-methoxyphenyl -5 (4) -phenyl imidazole,

M.P. 161163 (from toluene), from 5.94 g. of N-(4-methoxy-a-phenyl-phenacyl -propionamide;

2-isopropyl-4(5) (p methoxyphenyl) 5(4) phenylimidazole, M.P. l89191(from toluene), from 6.22 g. ofN-(4-methoxy-a-phenyl-phenacyl)-isobutyramide;

2-tert. butyl-4(5)-(p methoxyphenyl) 5 (4) phenylimidazole, M.P. 193194(from toluene), from 6.50 g. ofN-(4-methoxy-a-phenyl-phenacyl)-pivalamide;

2-cyclopropyl-4(5)-(p methoxyphenyl) 5(4) phenylimidazole, M.P. 192193(from toluene), from 6.18 g. of N(4-methoxy-a-phenyl-phenacyl)-cyclopropanecarboxamide;

2-tert. butyl-4,5-bis-(p-tolyl) imidazole, M.P. 204-206 (from toluene),from 6.46 g. of N [4 methyl-a-(ptolyl)-phenacyl-pivalamide;

2-tert. butyl-4,5-bis-(p-methoxyphenyl) imidazole, M.P.

167-168" (from benzene), from 7.10 g. of N-[4-methoxy-a-(p-methoxyphenyl -phenacyl] -pivalamide.

(b) The following fuither compounds may also be prepared analogously:

2-tert.butyl-4(5) (p methylsulphonylphenyl) 5(4)- phenyl-imidazole, M.P.215217, from of N-(4-methylsulphonyl-a-phenyl-phenacyl) -pivalamide;

2-tert.butyl-4(5) (p hydroxyphenyl) 5 (4) phenylimidazole, M.P.190-192", from 6.2 g. of N-(4-hydroxy-u-phenyl-phenacyl)-pivalamide;

2-tert.butyl-4( 5 (p methoxyphenyl 5 (4) chlorophenyl)imidazole, M.P.148-150", from 7.2 g. of N-[4-methoXy-u-(p-chlorophenyl)-phenacyl]-pivalamide.

The starting materials are produced as follows:

(c) An amount of 11 g. (0.036 mole) of 2-amino-4'- methoxy 2 (pmethoxyphenyl) acetophenone hydrochloride [produced according to G.Drehfahl and M. Hartmann, Ann., 589, 82-90 (1954), by reduction ofpanisil-monoxime] is suspended in 100 ml. of abs. benzene. After theaddition of 4.0 g. ,0.04 mole) of triethylamine, 4.72 g. (0.04 mole) ofvaleryl chloride in 10 ml. of absolute benzene are added dropwise, withice cooling and within 15 minutes, in a manner to ensure that theinternal temperature does not exceed 20. After another 10 minutes, afurther 4.0 g. (0.04 mole) of triethylamine are added dropwise, and thesuspension is stirred for 14 hours at 20-25; water is subsequentlyadded, and the suspension then diluted with ethyl acetate. The organicphase is separated, washed with water, 2 N sodium carbonate solution,saturated sodium chloride solution, and 2 N hydrochloric acid. Theresidue, obtained after a further neutral washing with saturated sodiumchloride solution, drying over sodium sulphate, and concentration byevaporation, is recrystallized from ethanol. The obtained N-[4-methoxy-a- (p-methoxyphenyl) -phenacyl] valeramide melts at -92;yield 7.5 g., 59% of the theoretical value. For further processing it isalso possible to use, instead of the crystallized product, theevaporation residue.

Obtained analogously are the following amides by acylation of 11.0 g.(0.036 mole) of 2-amino-4-methoxy- 2-(p-methoxyphenyl)acetophenone-hydrochloride with 0.040 mole of the corresponding acidchlorides:

N- [4-methoxy-u- (p-methoxyphenyl -phenacyl] -propionamide, M.P. -102(from benzene), with 3.70 g. of propionyl chloride;

N- [4-methoxy-a- (p-methoxyphenyl) -phenacyl] -isobutyramide, M.P. -127(from benzene), with 4.26 g. of isobutyryl chloride;

N [4-methoxy-u- (p-methoxyphenyl -phenacyl] -isovaleramide, M.P. 104-106(from benzene), with 4.82 g. of isovaleryl chloride;

N- [4-methoxy-a-p-methoxyphenyl) -phenacyl] -heptanamide, M.P. 98100(from ethanol/ether), with 5.94 g. of heptanoyl chloride;

N- [4-methoxy-a- (p-methoxyphenyl phenacyl] -2,2-

dimethylvaleramide, M.P. 75-77 (from benzene/ cyclohexane), with 5.94 g.of 2,2-dimethyl-valeryl chloride;

N- [4-methoxy-u- (p-methoxyphenyl) -phenacyl] -cyclopropanecarboxamide,M.P. 136139 (from ethanol), with 4.18 g. of cyclopropanecarbonylchloride.

Obtained analogously are also the following amides by acylation of 10.0g. (0.036 mole) of 2-amino-4-methoxy- 2-phenylacetophenone-hydrochloride[cf. (b) and (c) above] with 0.040 mole of the corresponding acidchlorides:

N-(4-methoxy-a-phenyl-phenacyl)-propionamide, M.P. 99-102 (from ethylacetate/petroleum ether), with 3.70 g. of propionyl chloride;

N-(4-methoxy-a-phenyl-phenacyl)-isobutyramide (crude product) with 4.26g. of isobutyryl chloride;

N-(4-methoxy-a-phenyl-phenacyl)-pivalamide (crude product) with 4.82 g.of pivalyl chloride;

N- (4-methoxy-a-phenyl-phenacyl -cyclopropanecarboxamide, M.P. -157(from benzene), with 4.18 g. of cyclopropanecarbonyl chloride.

Likewise analogously are obtained:

N- [4-rnethyl-a- (p-tolyl -phenacyl] -pivalamide (crude product) using9.92 g. (0.036 mole) of 2-amino-4'-methyl-2-(p-tolyl)-acetophenone-hydrochloride [cf. (b) and (c)] and 4.82g. of pivalyl chloride;

N- [4-methoxy-u- (p-methoxyphenyl -phenacyl] pivalamide, M.P. 99-101(from ethanol), using 11.0 g. of 2-amino-4'-methoxy-2-(p-methoxyphenyD-13 acetophenone-hydrochloride and 4.82 g. of pivalyl chloride.

(d) Analogously are obtained:

N (4 methylsulphonyl oz phenylphenacyl) pivalamide, M.P. 155-157 (fromtoluene), using 12.0 g. of 2 amino 4' methylsulphonyl 2 phenylacetophenom-hydrochloride and 5.2 g. of pivaloyl chloride, whereby thecorresponding amino ketone hydrochloride is obtained as follows: Anamount of 14.5 g. (0.053 mole) of4'-methylsulphonyl-2-phenyl-acetophenone is dissolved in 450 ml. ofethylene dichloride; the solution is heated to 35 and, within 20minutes, a solution of 8.6 g. of bromine in 20 ml. of ethylenedichloride added dropwise. The reaction mixture is subsequently stirredfor 2 hours at 20-25, and then concentrated in a rotary evaporator. Theresidue is recrystallized from alcohol. 2-bromo-4-methylsulphonyl-2-phenyl-acetophenone is obtained as white crystals,M.P. 158-160. [Obtained analogously is 2 bromo 4 methylsulphonyl 2 (pmethoxyphenyl)-acetophenone, M.P. 126-129, starting with 5.0 g. of4-methy1sulph0nyl2-(p-methoxyphenyl)acet0phen0ne and 2.64 g. of bromine]An amount of 7.0 g. (0.02 mole) of2-bromo-4'-methylsulphonyl-Z-phenylacetophenone is stirred with 2.94 g.(0.02 mole) of hexamethylene tetramine in 100 ml. of ethylene dichloridefor 24 hours at 20-25. The white precipitate is filtered off undersuction and the suction-filter-residue taken up in 80 ml. of abs.alcohol; to the mixture are added 20 ml. of concentrated hydrochloricacid, and the whole stirred for 2 hours at 20-25 and then for 3 hours at-5". The white crystals are filtered off, taken up in water, and thesuspension is made alkaline Wth 2 N sodium carbonate solution. The whitesuspension is extracted with ether. The organic phase is dried oversodium sulphate, and ethereal hydrochloric acid solution is added,whereby the desired 2amino-4-methylsulphonyl-2-phenylacetophenone-hydrochloride precipitatesas white crystals, M.P. 212-214.

The two amino ketone hydrochlorides not known hitherto are produced asfollows:

(e) Hydrogen chloride is passed at 20-25 into a suspension of 34.0 g.(0.15 mole) of 4'-methoxy-2-phenylacetophenone in 800 ml. of ether.After 30 minutes, 19.5 ml. of freshly distilled butyl nitriate are addeddropwise within 25 minutes. The flow of hydrogen chloride is stoppedafter a further 4 hours; the reaction mixture is then allowed to standfor ca. 15 hours, and afterwards filtered. The filtrate is extractedthree times with ice-cooled 2 N sodium hydroxide solution. The aqueousalkaline solution is neutralized, with ice cooling, using dilutehydrochloric acid, and then extracted with ethyl acetate. The organicphase is washed neutral with saturated sodium chloride solution, driedover sodium sulphate, and concentrated by evaporation. The residue iscrystallized from ethanol, whereby4'-methoxy-2-oximino-2-phenylacetophenone, M.P. 1l6-118, is obtained.

4-methyl-2-oximino-2-(p-tolyl)-acetophenone is produced analogouslystarting with 33.7 g. (0.15 mole) of 4-methyl-2- p-tolyl) -acetophenone.

(f) To the solution of 34.0 g. (0.133 mole) of4'-methoxy-2-oximino-2-phenyl-acetophenone in 300 ml. of ethanol and 100ml. of dioxane is added dropwise at 20- 25 within 30 minutes, a solutionof 146.4g. of tin(II)- chloride in 288 m1. of concentrated hydrochloricacid. The reaction mixture is stirred for one week at 20-25, andsubsequently poured into a mixture of 2 kg. of ice and 2.5 litres of 5 Nsodium hydroxide solution. The white mixture is extracted with ether,and the organic phase washed with saturated sodium chloride solution,and dried over sodium sulphate. From the filtered organic phase isprecipitated, with ethereal hydrogen chloride solution, thehydrochloride of 2-amino-4'-methoxy-2- phenyl-acetophenone, M.P. 234-236(from ethanol).

2 amino 4' methyl-Z-(p-tolyl)-acetophenone-hydrochloride is producedanalogously, starting with 33.7 g. (0.133 mole) of4-methyl-2-oximino-2-(p-tolyl)-acetophenone.

EXAMPLE 6 To a solution of 8.38 g. (0.0025 mole) of 2bromo-4'-methoxy-Z-(p-methoxyphenyl)-acetophenone in 40 ml. of chloroform areadded 3.68 g. (0.03 mole) of isobutyramidine-hydrochloride in 15 ml. ofwater. The solution of 2.9 g. (0.06 mole) of potassium hydroxide in 15ml. of water is added dropwise, with vigorous stirring and introductionof nitrogen, to the emulsion at 15-20, the whole reflux for 4-5 hours,and then poured still hot into a separating funnel. The lower organicphase is separated, washed with 2 N sodium carbonate solution andsaturated sodium chloride solution, dried over sodium sulphate, andconcentrated by evaporation. The residue is recrystallized from ethylacetate, and dried in high vacuum at whereby 2-isopropyl 4,5 bis-(p-methoxyphenyD-imidazole, M.P. l95l96 is obtained.

The following imidazoles are obtained in an analogous manner by using,instead of isobutyramidine-hydrochloride, 0.03 mole of the correspondingamidine hydrochlorides:

Likewise analogously obtained are the following imidazoles:

2 isopropyl 4(5) (p-methoxyphenyl) 5 (4) phenylimidazole, M.P. 189-l9l(from toluene), starting with 7.63 g. (0.025 mole) of2-bromo-4'-methoxy-2-phenylacetophenone and 3.68 g. (0.030 mole) ofisobutylamidine-hydrochloride;

2 tert.butyl 4(5) (p-methoxyphenyl) 5(4) phenylimidazole, M.-P. 193-194(from toluene), starting with 7.63 g. (0.025 mole) of2-bromo-4'-methoxy-2-phenylacetophenone, or the same amount of2-bromo-2-(pmethoxyphenyl)-acetophenone and 4.10 g. (0.030 mole) ofpivalamidine-hydrochloride;

2 cyclopropyl 4(5) (p-methoxyphenyD-S (4)-phenylimidazole, M.P. 192-193(from toluene), starting with 7.63 g. (0.025 mole) of2-bromo-4'-methoxy-2-phenylacetophenone and 3.62 g. (0.030 mole) ofcyclopropanecarboxamide-hydrochloride;

2 tert.butyl 4,5 bis-(p-tolyl)-imidazole, M.P. 204- 206 (from toluene),starting with 7.58 g. (0.025 mole) of 2 bromo 4 methyl-2-(p-tolyD-acetophenone and 4.10 g. (0.030 mole) of pivalamidinehydrochloride.

(b) The following further compounds may also be produced analogously:

2-tert.butyl-4(5 -(p-methylsulphonylphenyl) 5 (4)-phenylimidazole, M.P.215-217", starting with 8.83 g. (0.025 mole) of2-bromo-4-methylsulphonyl-2-phenyl-acetophenone and 4.10 g. (0.030 mole)of pivalamidine-hydrochloride;

2-tert.butyl-4(5)-(p-hydroxyphenyl) 5(4) phenyl-imidazole, M.P. 190-192,starting with 7.28 g. (0.025 mole) of 2bromo-4'-hydroxy-2-phenyl-acetophenone and 4.10 g. (0.030 mole) ofpivalamidine-hydrochloride;

2-tert.butyl-4(5)-(P-methoxyphenyl) 5(4) (m chloro phenyl)-imidazole,M.P. 169-171, starting with 8.48 g. (0.025 mole) of2-bromo-4'-methoxy-2-(m-chlorophenyl)acetophenone and 4.10 g. (0.030mole) of pivalamidine-hydrochloride;2-tert.butyl-4(5)-(p-methylsulphonylphenyl) (4)(pmethoxyphenyl)imidazole, M.P. 205207, starting with 9.6 g. (0.025mole) of 2-bromo-4'-methylsulphonyI-Z-(p-methoxyphenyl)-acetaphenone and4.10 g.

0.030 mole) of pivalamidine-hydrochloride.

EXAMPLE 7 An amount of 9.27 g. (0.03 mole) of 2-ethyl-4,5-bis-(p-methoxyphenyl)oxazole is heated with 97 g. of liquid ammonia and 64g. of formamide in an autoclave for 5 hours to 200. (The internalpressure rises to 185 atm.) After cooling, the reaction mixture ispoured into water, and extracted with ethyl acetate. The organic phaseis separated, washed until neutral with saturated sodium chloridesolution, and afterwards shaken with ml. of 1 N hydrochloric acid. Theinsoluble hydrochloride of the desired imidazole is filtered off undersuction, recrystallized from ethanol (M.P. 195-197"), suspended in ethylacetate, and shaken with aqueous ammonia. The organic phase isseparated, dried over sodium sulphate, and concentrated by evaporation.The residue is recrystallized from ethanol, whereby 2ethyl-4,5-bis-(p-methoxy)-imidazole, M.P. 170-172 is obtained.

(a) The following imidazoles are obtained in an analogous manner, byusing, instead of 2-ethyl-4,5-bis-(p-methoxyphenyl)oxazole, 0.03 mole ofthe corersponding oxazoles:

2-isopropyl-4,5-bis-(p-methoxyphenyl) imidazole, M.P.

195196 (from ethyl acetate), from 9.69 g. of2-isopropyl-4,5-bis-(p-metoxyphenyl)-oxazole;

2 isobutyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P. 166-168 (frombenzene), from 10.11 g. of 2-isobutyl- 4,5-bis-(p-methoxyphenyl)oxazole;

2 tert.-butyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P.

167168 (from benzene), from 10.11 g. of 2-tert.butyl-4,5-bis-(p-methoxyphenyl)-oxazole;

2 hexyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P. 145- 147 (fromtoluene), from 10.95 g. of 2-hexyl-4,5-bis (p-methoxyphenyl)oxazole;

2-cyclopropyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P.

189-19l (from toluene), from 9.61 g. of 2-cyclopropyl-4,5-bis-(p-methoxyphenyl oxazole;

2-isopropyl-4(5)-(p-methoxyphenyl) 5(4) phenyl-imidazole, M.P. 18919l(from toluene), from 8.97 g. of 2isopropyl-4-(p-methoxyphenyl)-5-phenyl-oxazole;

2 tert.butyl-4(5 (p-methoxyphenyl) -5 (4) -phenyl-imidazole, M.P. 193194(from toluene), from 9.21 g. of2-tert.butyl-4-(p-methoxypenyl)-5-penyl-oxazole;

2-cyclopropyl-4(5)-(p-methoxyphenyl) 5 (4) phenylimidazole, M.P. 192193(from toluene) from 8.73 g. of 2-cyclopropyl-4(p-methoxyphenyl) 5phenyl-ozazole;

2 tert.butyl-4,5-bis-(p-tolyl)-imidazole, M.P. 204-206" (from toluene),from 9.15 g. of 2-tert.butyl-4,5-bis-(ptoly1)-oxazole.

(b) The following further compounds may also be produced analogously:

2-tert.butyl-4(5)-(p-methylsulphonylphenyl 5 (4) phenyl-irnidazole, M.P.2l5217, from 10.65 g. of 2-tert.butyl-4-(p-methylsulphonylphenyl)-5-phenyl-oxazole;

2 tert.buty1-4 (5 (p-hydroxyphenyl) -5 (4 -phenyl-imidazole, M.P.190192, from 8.49 g. of2-tert-butyl-4-(phydroxyphenyl)-5-phenyl-oxazole;

2-tert.butyl-4(5)-(p-methoxyphenyl) 5(4) (p chlorophenyD-imidazole, M.P.148-150, from 10.45 g. of tert.butyl-4-(p-methoxyphenyl) 5 (pchlorophenyl)-oxazole.

The oxazoles required as starting materials are produced, for example,as follows:

(c) To the mixture of 13.60 g. (0.05 mole) of p-anisoin,

10 ml. of triethylamine and 100 ml. of abs. benzene is added dropwise,at 40 initial temperature, a solution of 6.5 g. (0.07 mole) of propionylchloride in 20 ml. of abs. benzene. The internal temperature therebyrises to ca. 70. The suspension is stirred for 5 hours at 50"; 50 ml. ofwater are then added, and stirring proceeds for one hour at 20-25 To thesuspension are then added 100 ml. of ethyl acetate, and the mixture iswashed successively with 2 N hydrochloric acid, water, 2 N sodiumcarbonate solution, and saturated sodium chloride solution. The organicphase is separated, dried with sodium sulphate, and then concentrated byevaporation, whereby crude p-anisoin-propionic acid ester remainsbehind.

(d) The crude p-anisoin-propionic acid ester obtained according to (a)is refluxed with 25 g. of ammonium acetate and 100 ml. of glacial aceticacid for 5 hours. The hot reaction solution is subsequently poured on toa mixture of 250 g. of ice and 200 ml. of concentrated aqueous ammoniasolution, and thereupon extracted with ethyl acetate. The organic phaseis washed with 2 N hydrochloric acid and saturated sodium chloridesolution, dried, and concentrated by evaporation. The residue iscrystallized from ethanol, whereby2-ethyl-4,5-bis-(p-methoxyphenyl)-oxazole, M.P. 8385, is obtained.Instead of the recrystallized substance, it is also possible for thecrude product to be further processed.

The following are obtained analogously to (c) and (d):

2-isopropyl-4,5-bis-(p-methoxyphenyl)-oxazole, M.P.

81 (from ethanol), starting with 13.60 g. (0.05 mole) of p-anisoin and7.5 g. (0.07 mole) of isobutyryl chloride;

2 isobutyl 4,5 bis-(p-methoxyphenyl)-oxazole (crude product), startingwith 13.60 g. (0.05 mole) of p-anisoin and 8.5 g. (0.07 mole) ofisovaleryl chloride;

2-tert.butyl-4,5-bis-(p-methoxyphenyl)-oxazole, M.P. 79-

81 (from petroleum ether), starting with 13.60 g. (0.05 mole) ofp-anisoin and 8.5 g. (0.07 mole) of pivaloyl chloride;

2-hexyl-4,5-bis-(p-methoxyphenyl)-oxazole (crude product), starting with13.60 g. (0.05 mole) of p-anisoin and 10.4 g. (0.07 mole) of heptanoylchloride;

2-cyclopropyl-4,5-bis-(p-methoxyphenyl) oxazole, M.P. 1l3114 (frommethanol), starting with 13.60 g. (0.05 mole of p-anisoin and 7.4 g.(0.07 mole) of cyclopropanecarbonyl chloride;

2-isopropyl-4-(p-methoxyphenyl)-5-pheny1-oxazole, M.P. 5859 (frompetroleum ether), starting with 12.10 g. 0.05 mole) of 4-methoxybenzoinand 7.5 g. (0.07 mole) of isobutyryl chloride;

2-tert.butyl-4-(p-methoxyphenyl)-5-phenyl-oxazole (crude product),starting with 12.10 g. (0.05 mole) of 4-methoxybenzoin and 8.5 g. (0.07mole) of pivaloyl chloride;

2 cyclopropyl 4 (p-methoxyphenyl)-5-phenyl-oxazole (crude product),starting with 12.10 g. (0.05 mole) of 4-methoxybenzoin and 7.4 g. (0.07mole) of cyclopropanecarbonyl chloride;

2-tert.butyl-4,5-bis (p-tolyl) oxazole, M.P. 128l30 (from petroleumether), starting with 12.0 g. (0.05 mole) of p-toluoin and 8.5 g. (0.07mole) of pivaloyl chloride.

(e) The following further compounds may also be prepared analogously:

2-tert.butyl-4-(p-methylsulphonylphenyl) 5 phenyloxazole, starting with14.5 g. (0.05 mole) of 4-methylsulphonylbenzoin and 8.5 g. of pivaloylchloride;

2-tert.-butyl-4-(p-hydroxyphenyl)-5-phenyl-oxazole, starting with 11.4g. (0.05 mole) of 4-hydroxybenzoin and 17.0 g. of pivaloyl chloride;

2 tert.butyl 4 (p-methoxyphenyl)-5- (p-chlorophenyl)- oxazole, startingwith 13.8 g. (0.05 mole) of 4-methoxy- 4'-chlorobenzoin and 8.5 g. ofpivaloyl chloride.

EXAMPLE 8 To a solution of 30.84 g. (0.10 mole) of 2-ethyl-4,5-bis-(p-methoxyphenyl)-irnidazole in 900 ml. of acetone are added at20-25 9.61 g. (6.5 ml., 0.10 mole) of 17 methane sulphonic acid, andstirring then proceeds for ca. 15 hours. The White crystals are filteredoff under suction. After recrystallization from ethanol/ether, theobtained 2-ethyl-4,S-bis-(p-methoxyphenyl) imidazolemethanesulphonatemelts at 149-151.

EXAMPLE 9 An amount of 15.0 g. of2-isopropyl-4,5-bis-(p-methoxyphenyl)-imidazole is taken up in 400 ml.of ethyl acetate and 100 ml. of ether, and filtered. The filtrate isshaken with 70 ml. of 2 N hydrochloric acid in a separating funnel. Theprecipitated hydrochloride is then filtered off under suction, and thesuction-filter residue dried for ca. 6 hours in high vacuum at 80; it isafterwards recrystallized from abs. ethanol/ether, and again dried, at110, under high vacuum. The obtained 2-isopropyl-4,5-lbis-(p-methoxyphenyl)-imidazolehydrochloride melts at 264-267".

EXAMPLE 10 The mixture of 5.8 g. (0.02 mole) of 4-methylsulphonylbenzil,1.7 g. (0.02 mole) of pivalaldehyde, 10.0 g. (0.13 mole) of ammoniumacetate and 50 ml. of glacial acetic acid is refluxed for 15 hours, andsubsequently poured, with vigorous stirring, on to 150 g. of ice. Theyellow solution is rendered slightly alkaline with aqueous ammoniasolution, and extracted with ethyl acetate. The organic phase isseparated, dried over sodium sulphate, and concentrated by evaporation.The residue is recrystallized from toluene, and dried under high vacuumat 110, whereby 2-tert.butyl4 [p- (methylsulphonyl) -phenyl]5(4)-phenyl-imidazole, M.P. 215-217, is obtained.

The following is obtained analogously: 2-isopropyl-4(5)-[p-(methylsulphonyl)-phenyl] 5(4) phenyl-irnidazole, M.P. 207-208(from toluene), starting with 5 .8 g. (0.02 mole) of4-methylsulphonylbenzil and 1.4 g. (0.02 mole) of isobutyraldehyde.

EXAMPLE 11 The mixture of 4.5 g. (0.02 mole) of 4-hydroxybenzil, 1.72 g.(0.02 mole) of pivalaldehyde, 10.0 g. (0.13 mole) of ammonium acetateand 60 ml. of glacial actic acid is refluxed for 18 hours, andsubsequently poured, with vigorous stirring, into a mixture of 150 g. ofice and 120 ml. of concentrated aqueous ammonia solution. The crystalmass is extracted with ethyl acetate, the organic phase washed untilneutral with saturated sodium chloride solution, dried over sodiumsulphate, and concentrated by evaporation. The residue is crystallizedfrom ethyl acetate/petroleum ether, and dried under high vacuum at 110,whereby 2-tert.butyl-4(5) (p-hydroxyphenyl)- 5(4)-phenyl-imidazole, M.P.190-192, is obtained.

The following are obtained analogously:

2 tert.butyl 4(5) (p methoxyphenyl) 5(4) (phydroxyphenyl)-imidazole,M.P. 216-218" from ether/ pentane; starting with 5.1 g. (0.02 mole) of4-hydroxy- 4'-methoxybenzil and 1.72 g. (0.02 mole) of pivalaldehyde;

2 tert.butyl 4(5) (p hydroxyphenyl) 5(4)-(mtolyl) imidazole, M.P.227-228 from toluene/ cyclohexane; starting with 4.8 g. (0.02 mole) of4- hdyroxy 3 methylbenzil and 1.72 g. (0.02 mole) of pivalaldehyde;

2 tert.butyl 4(5) (p hydroxyphenyl) 5(4)-(mchlorophenyl)-imidazole, M.P. 238-240 from toluene/ cyclohexane; starting with 5.2 g. (0.02 mole)of 4- hydroxy-3'-chlorobenzil and 1.72 g. (0.02 mole) of pivalaldehyde.

The starting materials for the two last-mentioned compounds are obtainedas follows:

The mixture of 9.5 g. of 4-methoxy-3'-chlorobenzil, 50 ml. of glacialacetic acid and 100 ml. of 48% hydrogen Ibromide is refluxed for 20hours, and subsequently poured into water. The thus obtained suspensionis extracted with ether. The organic phase is washed three times with 2N 18 sodium carbonate solution, dried over sodium sulphate, andconcentrated by evaporation. The residue is recrystallized fromether/petroleum ether. The thus purified 4-hydroxy-3-chlorobenzil meltsat 154-155 4-hydroxy-3-methylbenzil, M.P. 120-121 (from ether/ petroleumether), is obtained analogously, starting with 14.5 g. of4-methoxy-3-methylbenzil.

EXAMPLE 12 The mixture of 1.0 g. of 4-methylsulphonyl-4'-methoxybenzil,0.3 g. of pivalaldehyde, 2.0 g. of ammonium acetate and 30 ml. ofglacial acetic acid is refluxed for 14 hours, and subsequently poured,with vigorous stirring, onto g. of ice. The yellow solution is renderedweakly alkaline with ammonia, and extracted with ethyl acetate.

The organic phase is separated, dried over sodium sulphate, andconcentrated by evaporation. The residue is recrystallized fromalcohol/cyclohexane, and dried under high vacuum at whereby 2-tert.butyl4(5) [p- (methylsulphonyl) phenyl1-5(4)-p-(methyloxyphenyl)- imidazole,M.P. 205-2=07, is obtained.

The starting materials are obtained as follows:

(a) 4-methylthio-2 (p methoxyphenyl) acetophenone.To the mixture of 50g. of thionanisole, 92.5 g. of 4-methoxyphenylacetic acid chloride and360 ml. of tetrachloroethane are added in portions at 0-5 within 30minutes, 69.4 g. of aluminium chloride. The reaction mixture is firstlystirred for 7 hours at 0-5, and then for 10 hours at 20-25 The blackmass is subsequently poured on to a mixture of ice and concentratedhydrochloric acid, the whole well stirred, and allowed to standovernight. The organic lower phase is then separated and concentrated ina rotary evaporator. The residue is dissolved in boiling alcohol and,with stirring, slowly cooled. The solution is separated from the darkoil initially precipitating. On further cooling is obtained crystalline4'-methylthio- 2- (p-methoxyphenyl) acetophenone, M.P. 121-123 (b)4'-methylsulphonyl-2-(p-methoxyphenyl)-acetophenone.-The mixture of 5 g.of 4'-methylthio-2-(p-methoxyphenyl)-acetophenone, 100 ml. of glacialacetic acid and 10 ml. of 30% hydrogen peroxide is stirred for 22 hoursat 20-25 and subsequently poured onto 700 ml. of water. The whitecrystals are filtered 01f under suction, and recrystallized from alittle alcohol, M.P. 162-163.

(c) 4-methylsulphonyl-4'-methoxy-benzil.-The mixture of 1.5 g. of4'-methylsulphonyl-2-(p-methoxyphenyD- acetophenone, 0.6 g. of seleniumdioxide and 30 ml. of glacial acetic acid is refluxed for 26 hours; itis subsequently filtered hot and poured on to 800 ml. of Water. The thusobtained crystals are filtered ofl under suction, dried andrecrystallized from alcohol/pentane. The4-methylsulphonyl-4'-methoxybenzil melts at 131-133 EXAMPLE 13 Thefollowing compounds were produced analogously to Example 1(a):

2-isopropyl-4(5)-(p-methoxyphenyl) 5(4) (p tolyl)- imidazole, M.P.200-201", from 12.7 g. of 4-methoxy- 4'-methylbenzil and 3.96 g. ofisobutyraldehyde;

2-(1-methylpropyl)-4,5-bis (p-methoxyphenyl) imidazole, M.P. -171", from13.5 g. of p-anisil and 4.73 g. of l-methylbutyraldehyde;

2-(1-ethylpropyl)-4,5-bis-(p-methoxyphenyl) imidazole,

M.P. 168-169", from 13.5 g. of p-anisil and 5.5 g. of 1-ethylbutyraldehyde;

2-cyclopentyl-4,5-bis-(p-methoxyphenyl)-imidazole, M.P.

170-172", from 13.5 g. of p-anisil and 5.5 g. ofcyclopentanecarboxaldehyde;

2-cyclobutyl-4,5-bis-( p-methoxyphenyl -imidazole, M.P.

176-178", from 13.5 g. of p-anisil and 4.62 g. ofcyclobutylcarboxaldehyde;

2-tert.butyl-4(5)-(p-methoxyphenyl)-5(4) (o chlorophenyD-imidazole, M.P.188-190", from 13.7 g. of 4- methoxy-2'-chlorobenzil and 4.73 g. ofpivalaldehyde;

What is claimed is:

1. A pharmaceutical composition comprising an analgesic, antiphlogisticor antipyretic effective amount of a compound of the formula wherein Ris alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,

R, is methoxy, methyl, or methylsulfonyl, and

R is methoxy, methyl, hydrogen or chloro, or a pharmaceuticallyacceptable acid addition salt thereof and a pharmaceutical carriertherefore.

2. A composition as claimed in claim 1, wherein the active ingredient is2-ethyl-4,5 bis (p-methoxyphenyl)- imidazole.

3. A composition claimed in claim 1, wherein the active ingredient is2-isopropyl 4,5-bis (p-methoxyphenyD- imidazole.

4. A composition as claimed in claim 1, wherein the 20 active ingredientis 2 cyclopropyl 4,5 bis-(p-methoxypheny1)-imidazole.

5. A composition as claimed in claim 1, wherein the active ingredient is2-tert.butyl-4(5 )-[p-(methylsulfonyl)- phenyl] -5 (4)-phenyl-imidaz0le.

6. A composition as claimed in claim 1, wherein the active ingredient is2-tert.butyl-4(5)-(p-hydroxyphenyl)- 5 (4) -phenyl-imidazole.

7. The method of producing an analgesic elfect in a mammal sufleringfrom pain which comprises administering to said mammal an analgesicallyelfective amount of a compound according to claim 1.

8. The method of producing an antiphlogistic effect in a mammalsuffering from inflammation which comprises administering to said mammalan antiphlogistically elfective amount of a compound according to claim1.

9. The method of producing an antipyretic effect in a mammal sulferingfrom fever which comprises administering to said mammal anantipyretically effective amount of a compound according to claim 1.

References Cited Carrara et al.: Chem. Abst., vol. 40, col. 7241 (1946).

Radziszewski: Chem. Abst., vol. 4, pp. 2265-6 (1910).

Novelli et al.: Chem. Abst., vol. 38, col. 2957 (1944).

Schubert et al.: Chem. Abst., vol. 53, cols. 15061-2 (1959).

Delzenne et al.: Chem. Abst., vol. 71, No. 39 628b (1969).

Neugebauer et al.: Chem. Abst., vol. 56, col. 3065 (1962).

STANLEY I. FRIEDMAN, Primary Examiner us. 01. X.R. 260-309

